autosomal recessive Alport syndrome

Summary

autosomal recessive Alport syndrome (MONDO:0008762) is a disease caused by variants in COL4A3 and COL4A4, with 5 cohort genes and 2 clinical trials. The dominant Reactome pathway is NCAM1 interactions (3 cohort genes). Top therapeutic interventions include elx-02.

At a glance

• Causal genes: COL4A3 (GenCC Definitive), COL4A4 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,413
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive Alport syndrome
Mondo ID	MONDO:0008762
OMIM	203780
Orphanet	88919
DOID	DOID:0110033
SNOMED CT	717767009
UMLS	C4746745
MedGen	1648334
GARD	0000625
MedDRA	10001843
Is cancer (heuristic)	no

Also known as: Alport syndrome 2, autosomal recessive · Alport syndrome autosomal recessive · Alport syndrome recessive type · Alport syndrome, autosomal recessive · nephropathy and deafness

Data availability: 1,413 ClinVar variants · 11 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive Alport syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

161 likely pathogenic, 123 conflicting classifications of pathogenicity, 92 uncertain significance, 61 likely benign, 57 pathogenic/likely pathogenic, 49 benign, 35 pathogenic, 22 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075091	NM_000091.5(COL4A3):c.92_95dup (p.Lys34fs)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1185625	NM_000091.5(COL4A3):c.2439del (p.Arg814fs)	COL4A3	Pathogenic	no assertion criteria provided
1297071	NM_000091.5(COL4A3):c.4318del (p.Thr1440fs)	COL4A3	Pathogenic	no assertion criteria provided
1422757	NM_000091.5(COL4A3):c.1262del (p.Gly421fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451392	NM_000091.5(COL4A3):c.1992del (p.Gly665fs)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455985	NM_000091.5(COL4A3):c.4001G>A (p.Gly1334Glu)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1512833	NM_000091.5(COL4A3):c.2330G>T (p.Gly777Val)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687414	NM_000091.5(COL4A3):c.4114C>T (p.Gln1372Ter)	COL4A3	Pathogenic	criteria provided, single submitter
1724015	NM_000091.5(COL4A3):c.4207G>T (p.Gly1403Ter)	COL4A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17484	NM_000091.5(COL4A3):c.4441C>T (p.Arg1481Ter)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
17485	NM_000091.5(COL4A3):c.4571C>G (p.Ser1524Ter)	COL4A3	Pathogenic	criteria provided, single submitter
17492	NM_000091.5(COL4A3):c.3499G>A (p.Gly1167Arg)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
192299	NM_000091.5(COL4A3):c.40_63del (p.Leu14_Leu21del)	COL4A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2444275	NM_000091.5(COL4A3):c.4812C>A (p.Cys1604Ter)	COL4A3	Pathogenic	criteria provided, single submitter
1029644	NM_000092.5(COL4A4):c.3214+1G>T	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066915	NM_000092.5(COL4A4):c.559-2A>G	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067311	NM_000092.5(COL4A4):c.193-2A>C	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068082	NM_000092.5(COL4A4):c.4717del (p.Ala1573fs)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069400	NM_000092.5(COL4A4):c.3319_3358del (p.Leu1107fs)	COL4A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1072799	NM_000092.5(COL4A4):c.4544_4556del (p.Pro1515fs)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073781	NM_000092.5(COL4A4):c.4449_4450dup (p.Met1484fs)	COL4A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1074209	NM_000092.5(COL4A4):c.3310_3313dup (p.Gln1105fs)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075428	NM_000092.5(COL4A4):c.4953G>A (p.Trp1651Ter)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179086	NM_000092.5(COL4A4):c.3882_3883del (p.Cys1294fs)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179194	NM_000092.5(COL4A4):c.1785dup (p.Gly596fs)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1219193	NM_000092.5(COL4A4):c.1145G>C (p.Gly382Ala)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322133	NM_000092.5(COL4A4):c.1531C>T (p.Gln511Ter)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333430	NM_000092.5(COL4A4):c.1099+1G>T	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333646	NM_000092.5(COL4A4):c.2869G>A (p.Gly957Arg)	COL4A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342006	NM_000092.5(COL4A4):c.4720C>T (p.Gln1574Ter)	COL4A4	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
COL4A3	Definitive	Semidominant	Alport syndrome	12
COL4A4	Definitive	Autosomal recessive	autosomal recessive Alport syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL4A3	Orphanet:653722	Digenic Alport syndrome
COL4A3	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
COL4A3	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A3	Orphanet:88919	Autosomal recessive Alport syndrome
COL4A4	Orphanet:653722	Digenic Alport syndrome
COL4A4	Orphanet:88918	Autosomal dominant Alport syndrome
COL4A4	Orphanet:88919	Autosomal recessive Alport syndrome
CACNA1D	Orphanet:324321	Sinoatrial node dysfunction and deafness
CACNA1D	Orphanet:369929	Primary hyperaldosteronism-seizures-neurological abnormalities syndrome
LMX1B	Orphanet:2613	Nail-patella-like renal disease
LMX1B	Orphanet:2614	Nail-patella syndrome
LMX1B	Orphanet:495818	9q33.3q34.11 microdeletion syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL4A3	HGNC:2204	ENSG00000169031	Q01955	Collagen alpha-3(IV) chain	gencc,clinvar
COL4A4	HGNC:2206	ENSG00000081052	P53420	Collagen alpha-4(IV) chain	gencc,clinvar
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	clinvar
MFF-DT	HGNC:41067	ENSG00000236432		MFF divergent transcript	clinvar
LMX1B	HGNC:6654	ENSG00000136944	O60663	LIM homeobox transcription factor 1-beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL4A3	Collagen alpha-3(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL4A4	Collagen alpha-4(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
LMX1B	LIM homeobox transcription factor 1-beta	Transcription factor involved in the regulation of podocyte-expressed genes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	22.3×	0.132
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL4A3	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL4A4	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu
MFF-DT	Other/Unknown	no
LMX1B	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
retina	1
skeletal muscle tissue of biceps brachii	1
metanephros cortex	1
renal medulla	1
adrenal tissue	1
buccal mucosa cell	1
right lung	1
bone marrow cell	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL4A3	233	broad	marker	skeletal muscle tissue of biceps brachii, pigmented layer of retina, retina
COL4A4	187	broad	marker	renal medulla, metanephros cortex, pigmented layer of retina
CACNA1D	219	broad	marker	buccal mucosa cell, adrenal tissue, right lung
MFF-DT	158		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, bone marrow cell
LMX1B	74	broad	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1D	2,318
COL4A3	1,671
LMX1B	1,514
COL4A4	1,243
MFF-DT	0

Intra-cohort edges

A	B	Sources
COL4A3	COL4A4	string_interaction
COL4A3	LMX1B	string_interaction
COL4A4	LMX1B	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1D	Q01668	6
COL4A3	Q01955	2
COL4A4	P53420	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMX1B	O60663	70.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 5 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NCAM1 interactions	3	248.3×	2e-06	COL4A3, COL4A4, CACNA1D
Anchoring fibril formation	2	507.6×	5e-05	COL4A3, COL4A4
Fibronectin matrix formation	2	380.7×	5e-05	COL4A3, COL4A4
Crosslinking of collagen fibrils	2	380.7×	5e-05	COL4A3, COL4A4
Attachment of bacteria to epithelial cells	2	331.0×	6e-05	COL4A3, COL4A4
Laminin interactions	2	253.8×	8e-05	COL4A3, COL4A4
Collagen chain trimerization	2	173.0×	1e-04	COL4A3, COL4A4
Signaling by PDGF	2	169.2×	1e-04	COL4A3, COL4A4
Assembly of collagen fibrils and other multimeric structures	2	133.6×	2e-04	COL4A3, COL4A4
Collagen degradation	2	117.1×	2e-04	COL4A3, COL4A4
Collagen biosynthesis and modifying enzymes	2	113.6×	2e-04	COL4A3, COL4A4
Non-integrin membrane-ECM interactions	2	102.9×	3e-04	COL4A3, COL4A4
ECM proteoglycans	2	100.2×	3e-04	COL4A3, COL4A4
Integrin cell surface interactions	2	89.6×	3e-04	COL4A3, COL4A4
Adrenaline,noradrenaline inhibits insulin secretion	1	131.3×	0.013	CACNA1D
Sensory processing of sound	1	102.9×	0.015	CACNA1D
NCAM signaling for neurite out-growth	1	90.6×	0.016	CACNA1D
Regulation of insulin secretion	1	73.2×	0.019	CACNA1D
Integration of energy metabolism	1	58.6×	0.022	CACNA1D
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.023	CACNA1D
Sensory Perception	1	31.7×	0.037	CACNA1D
Axon guidance	1	15.1×	0.074	CACNA1D
Nervous system development	1	14.3×	0.074	CACNA1D
Developmental Biology	1	4.8×	0.202	CACNA1D
Metabolism	1	3.9×	0.237	CACNA1D

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glomerular basement membrane development	2	766.0×	7e-05	COL4A3, COL4A4
collagen fibril organization	2	112.3×	0.002	COL4A3, COL4A4
sensory perception of sound	2	50.5×	0.006	COL4A3, CACNA1D
positive regulation of adenylate cyclase activity	1	842.6×	0.006	CACNA1D
membrane depolarization during SA node cell action potential	1	842.6×	0.006	CACNA1D
negative regulation of vascular endothelial cell proliferation	1	842.6×	0.006	COL4A3
regulation of atrial cardiac muscle cell membrane repolarization	1	601.9×	0.007	CACNA1D
membrane depolarization during cardiac muscle cell action potential	1	351.1×	0.009	CACNA1D
collagen-activated tyrosine kinase receptor signaling pathway	1	324.1×	0.009	COL4A3
endothelial cell apoptotic process	1	324.1×	0.009	COL4A3
calcium ion import	1	200.6×	0.013	CACNA1D
cardiac muscle cell action potential involved in contraction	1	175.5×	0.013	CACNA1D
dopaminergic neuron differentiation	1	156.0×	0.013	LMX1B
regulation of potassium ion transmembrane transport	1	156.0×	0.013	CACNA1D
positive regulation of calcium ion transport	1	145.3×	0.013	CACNA1D
calcium ion import across plasma membrane	1	135.9×	0.013	CACNA1D
dorsal/ventral pattern formation	1	105.3×	0.016	LMX1B
regulation of heart rate by cardiac conduction	1	93.6×	0.017	CACNA1D
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	84.3×	0.018	CACNA1D
calcium ion transmembrane transport	1	52.7×	0.027	CACNA1D
calcium ion transport	1	45.3×	0.030	CACNA1D
negative regulation of angiogenesis	1	42.1×	0.031	COL4A3
neuron differentiation	1	25.1×	0.050	LMX1B
cell surface receptor signaling pathway	1	16.0×	0.074	COL4A3
negative regulation of cell population proliferation	1	10.5×	0.106	COL4A3
cell adhesion	1	9.4×	0.114	COL4A3
regulation of DNA-templated transcription	1	7.9×	0.130	LMX1B
positive regulation of transcription by RNA polymerase II	1	3.7×	0.252	LMX1B
regulation of transcription by RNA polymerase II	1	2.9×	0.302	LMX1B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 4

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CACNA1D	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1D	48	4
COL4A3	0	0
COL4A4	0	0
MFF-DT	0	0
LMX1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1D
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CACNA1D	233

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	CACNA1D
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1D
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	COL4A3, COL4A4, MFF-DT, LMX1B

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL4A3	0	—
COL4A4	0	—
MFF-DT	0	—
LMX1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07523581	PHASE2	NOT_YET_RECRUITING	EXACT Study: A Blinded Study in Patients With Alport Syndrome to Evaluate Exaluren Efficacy and Safety
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELX-02	2	1